In investigations bearing on the status of brain neurotransmitter systems in patients with affective disorders, new evidence suggesting decreased alpha-adrenergic receptor responsiveness in some patients with depression has been obtained. Several intensive case investigations were made of patients who may represent prototypes of a depressive subgroup with increased noradrenergic availability and decreased noradrenergic receptor responsivity. In studies of the cholinergic neurotransmitter system, depressive-type symptoms were identified following physostigmine administration in normals. The development of these symptoms correlated with beta-endorphin, cortisol and prolactin changes, perhaps representing a state of hypersensitivity in the hypothalamic-pituitary axis in susceptible individuals.